IDENTIFICATION OF REGIONS, GENES, AND GENETIC VARIANTS ASSOCIATED WITH ASTHMA IN CHILDREN.
Name: VALDEMIR PEREIRA DE SOUSA
Publication date: 30/04/2026
Examining board:
Name |
Role |
|---|---|
| ESTEVÃO CARLOS SILVA BARCELOS | Examinador Externo |
| FLAVIA DE PAULA | Examinador Interno |
| FLAVIA IMBROISI VALLE ERRERA | Presidente |
| SÉRGIO NERY SIMÕES | Examinador Externo |
| SONIA ALVES GOUVEA | Examinador Interno |
Summary: Asthma is a chronic, heterogeneous, and highly prevalent respiratory disease resulting from the interaction between genetic and environmental factors. The translation of genetic findings into clinical biomarkers remains limited and requires integrative approaches that capture the disease's complex, polygenic, and predominantly regulatory genetic architecture. This thesis investigated regions, genes, and genetic variants associated with pediatric asthma, with emphasis on functional impact and potential applicability as biomarkers, organized into four complementary fronts: an integrative review on copy number variations (CNVs) and asthma; functional in silico prioritization of variants in the ADRB2 gene; an association study of SNPs rs1042713 and rs1042714 with clinical and laboratory phenotypes in a cohort of children and adolescents from southeastern Brazil; and a transcriptomic meta-analysis of the pediatric nasal epithelium. The integrative review on CNVs identified structural variations across 12 distinct chromosomes, with 30 genes associated with disease phenotypes, of which 11 harbored significant expression quantitative trait loci (eQTLs). TPSAB1, ADAM8, and HLA-DQA1 stood out as candidates with the greatest functional plausibility. The functional in silico prioritization selected 13 ADRB2 variants with functional annotation, highlighting rs1042711, rs1042713, rs1042714, and rs1801704 as the loci with the strongest integrated regulatory and pharmacogenomic support, and underscoring the value of systematic prioritization as a strategy to guide functional and pharmacogenetic studies. In the pediatric cohort association study (n = 360), rs1042713 and rs1042714 showed nominal signals of association with pre-bronchodilator lung function parameters and IgG, classified as exploratory after Bonferroni correction, a result consistent with the positioning of these polymorphisms as modulators of specific subphenotypes. The transcriptomic meta-analysis of the nasal epithelium, conducted from three independent datasets (n = 861 samples), identified a reproducible signature of nine differentially expressed genes under stringent criteria – CST1, CST2, CST4, CLCA1, POSTN, ITLN1, CPA3, TPSAB1, and TPSB2 – all overexpressed in children with asthma and convergent across three distinct analytical approaches, delineating an epithelial program characterized by type 2 inflammation, secretory remodeling, and an intraepithelial mast cell component. Taken together, the results reinforce that identifying biomarkers of pediatric asthma requires an integrative approach that combines critical literature review, bioinformatic prioritization, clinical cohort validation, and transcriptomic synthesis, and that progress toward precision medicine in this context depends on the progressive construction of multimodal panels evaluated in larger, multi-ancestry cohorts with functional validation.
